Multiple sclerosis (MS) is the most common chronic autoimmune disease of the central nervous system. The majority of patients diagnosed with MS have the relapsing-remitting form of the disease (RRMS). Relapses, defined as subacute aggravation of neurologic symptoms, determine clinical activity. Patients regularly remit days to weeks after relapse and either recover completely or are left with residual disability. After many years, some but not all patients convert to a progressive form where disability accumulates over time independent from relapses (secondary progressive MS). A few (10%-20%) patients show a progressive MS course from the beginning (primary progressive MS). The progressive MS course is primarily responsible for permanent neurological dysfunction. However, the factors determining the progressive disease course are unknown. Accordingly, clinically, no singular biomarkers exist to ascertain a disease course other than relapses and clinical progression themselves. Most importantly, and unlike RRMS, progressive MS lacks effective therapies causing great adversity for affected patients. A biomarker that could readily discriminate between the two forms would have great utility in speeding diagnosis, especially of the progressive form, potentially saving patients from ineffective and potentially harmful therapies.
One previous study, described in Dickens A M, Larkin J R, Griffin J L, et al. “A type 2 biomarker separates relapsing-remitting from secondary progressive multiple sclerosis,” Neurology 2014; 83(17):1492-9, demonstrates that serum markers can be used to discriminate between the MS subtypes. However, this study relied on multiple metabolite profiles and computational models over full mass spectrometry spectra to achieve discrimination between RRMS and progressive MS. Single predictive biomarkers were not discovered.
In all metazoans, cell surface and secreted proteins are modified by post-translational addition of complex carbohydrates in the endoplasmic reticulum, forming glycoproteins in the N-glycosylation pathway. Branching complexity and number of N-glycans per protein molecule influence the concentration and endocytosis of surface glycoproteins. The synthesis rate of these complex carbohydrates is controlled by enzymatic activity in the endoplasmic reticulum and metabolic supply of substrates. The primary substrate of this pathway is N-acetylglucosamine (GlcNAc,), which is built into complex glycans by the Mgat enzyme family. Genetically induced alterations in Asn (N)-linked protein glycosylation has been shown to promote T cell mediated inflammatory demyelination as well as neurodegeneration. Oral supplementation of mice with GlcNAc has been shown to inhibit pro-inflammatory T cell responses in models of MS by enhancing N-glycan branching via increased substrate supply to Golgi glycosylation enzymes. Extracellular GlcNAc from dietary sources enters cells through macropinocytosis and is then salvaged into the hexosamine pathway for production of UDP-GlcNAc. It is further believed that ER-associated degradation may recycle GlcNAc within cells.
Despite the demonstrated physiological importance of GlcNAc, including its role in MS biology, it has not been previously established in the prior art whether GlcNAc is a natural constituent of human blood serum, and what association, if any, exists between GlcNAc serum levels and MS status or other measures of neurodegeneration.